The central tenet of regenerative medicine is to unlock the genetic programs that promote natural tissue regeneration. However, a major roadblock to achieving this reality is our lack of understanding of the genetic mechanisms that underscore complex tissue regeneration. Appendages -limbs, tail, and fins -are the most studied model organs in non-mammalian regeneration research based on the accessibility of the organs, as well as the efficiency and near perfection of restoration of a three-dimensional tissue comprised of many cell types. While appendage regeneration in mammals is restricted to the distal tips of digits, the zebrafish has maintained an enhanced capacity to regenerate multiple appendage tissues, including bone, nerves, blood vessels, epidermis and pigment cells. Our research program exploits the experimental and genetic prowess of the zebrafish to address two fundamental questions that underscore appendage regeneration. What molecular pathways regulate the natural cellular reprogramming from differentiated, quiescent tissues into highly proliferative, regenerative cells in response to injury? Is there is a core regulatory cascade that defines regenerative outgrowth and patterning during tissue replacement. Specifically, we will test the hypothesis that microRNAs play key roles in the initiation and maintenance of proliferative progenitor tissue during appendage regeneration. Understanding which specific molecular programs by which nonmammalian vertebrate model systems faithfully regrow complex organs will provide the basis for potential regenerative therapies.